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An essential role for dNTP homeostasis following CDK-induced replication stress

Pai, C-C; Hsu, K-F; Durley, SC; Keszthelyi, A; Kearsey, SE; Rallis, C; Folkes, LK; ... Humphrey, TC; + view all (2019) An essential role for dNTP homeostasis following CDK-induced replication stress. Journal of Cell Science , 132 (6) , Article jcs226969. 10.1242/jcs.226969. Green open access

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Abstract

Replication stress is a common feature of cancer cells, and thus a potentially important therapeutic target. Here we show that CDK-induced replication stress is synthetic lethal with mutations disrupting dNTP homeostasis in fission yeast. Wee1 inactivation leads to increased dNTP demand and replication stress through CDK-induced firing of dormant replication origins. Subsequent dNTP depletion leads to inefficient DNA replication, DNA damage, and to genome instability. Cells respond to this replication stress by increasing dNTP supply through Set2-dependent MBF-induced expression of Cdc22, the catalytic subunit of ribonucleotide reductase (RNR). Disrupting dNTP synthesis following Wee1 inactivation, through abrogating Set2-dependent H3K36 tri-methylation or DNA integrity checkpoint inactivation results in critically low dNTP levels, replication collapse and cell death, which can be rescued by increasing dNTP levels. These findings support a 'dNTP supply and demand' model in which maintaining dNTP homeostasis is essential to prevent replication catastrophe in response to CDK-induced replication stress.

Type: Article
Title: An essential role for dNTP homeostasis following CDK-induced replication stress
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1242/jcs.226969
Publisher version: http://doi.org/10.1242/jcs.226969
Language: English
Additional information: Copyright © 2019. Published by The Company of Biologists Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
Keywords: CDK, Histone H3K36 modification, MBF, Schizosaccharomyces pombe, Set2, Synthetic lethality, Wee1
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Genetics, Evolution and Environment
URI: https://discovery.ucl.ac.uk/id/eprint/10067374
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